ZNF334 truncation mutation drives cold-induced autoinflammation.

The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and Hsp90, diminished the endogenous levels of the cold stress regulators Hsp90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an Hsp90 inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and Hsp90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.